Androgens have been associated with the progression of many diseases such as prostate cancer, benign prostate hypertrophy, male alopecia, acne, and breast cancer, etc. Androgens execute their functions through binding to the androgen receptor (AR) that then regulates gene transcription in the cell nucleus. AR receptor is a member of the nuclear receptor superfamily that acts as a ligand-dependant transcription factor. AR is expressed mainly in androgen target tissue such as prostate, skeletal muscle, liver, skin and CNS, with the highest expression observed in the prostate. At the cellular level, unbound AR is located mainly in the cytoplasm where it is associated with a complex of heat shock proteins, mainly through interactions with the ligand binding domain (LBD). Upon ligand binding, AR enters the nucleus and activates target genes involved in diverse biological processes such as proliferation, differentiation, apoptosis and secretion. Various AR ligands have been discovered and developed for the treatment of muscle wasting, anemia, benign prostate hyperplasia and prostate cancers (Gao W et al., Drug Discov Today 2007; 12:241-248).
Prostate cancer (PCa) is the most common lethal non-cutaneous malignancy in many Western countries and androgen is one of the major factors influencing PCa development (Hendriksen P J et al., Cancer Res 2006: 66:5012-20). Androgen-AR activity has been tightly associated with the growth, differentiation and even carcinogenesis of the prostate (Culig Z. Urology 2003; 62:21-6; Heinlein C A et al., Endocr Rev 2004; 25:276-308). Furthermore, expression of AR protein is detected in nearly all prostate cancers (PCa) including those of distant metastases and ablation-resistant cases (Shah R B et al., Cancer Res 2004; 64:9209-06). AR also up-regulates the gene transcription of prostate specific antigen (PSA) which is the most widely used serological biomarker of PCa for both diagnosis and therapeutic assessment (Balk SP et al., J Clin Oncol 2003; 21:383-91; Cleutjens K B et al., Mol Endocrinol 1997; 11:148-61). It is understood that signaling pathways mediated by androgens and AR are essential for both normal and malignant prostate cells, although there are differences between these two states of prostate cells (Hendriksen P J et al., Cancer Res 2006; 66:5012-20; Denmeade S R et al., Prostate 1996; 28:251-65). At initial diagnosis, most PCa responds to androgen ablation therapy, which prevents the production or blocks the action of androgens, and inhibits prostate cancer growth (Craft N et al., Cancer Res 1999; 59:5030-6). However, cells eventually become androgen-independent or hormone-resistant, and tumors metastasize as the patient's disease advances. This is likely due to the fact that after the development of hormone resistance, many PCa still express AR, which continues to promote PCa progression. Therefore, targeting AR activity in cancerous prostate cells may be a more effective way for treating prostate cancer as AR is involved at different stages of the disease. In addition, inhibiting AR activity might eventually become beneficial for treating other types of AR-associated diseases such as male alopecia, acne, and breast cancer, etc. Nonetheless, currently existing antiandrogen drugs, such as flutamide, niutamide, and bicalutamide, induce severe side effects and are palliative or ineffective towards terminal prostate cancers Therefore, there is an urgent need to develop or search more effective therapeutic compounds for both prostate cancer and for other diseases associated with AR activity.
It is accordingly an object of the present invention to provide novel methods of inhibiting AR comprising the use of certain types of diterpenes. While the diterpenes disclosed in the present invention have been previously identified, they have been associated with other biological activities such as anti-microbial, anti-proliferative and cytotoxic activities (Chao K P et al., Planta Med 2005; 71:300-305; Iwamoto M et al., Planta Med 2003; 69: 69-72; Politi M et al., Planta Med 2003; 69:468-70) and one of them was reported to have no biological effect (Politi M et al., Planta Med 2003; 69:468-70). Here, these diterpenes are for the first-time reported to suppress AR activity in human PCa cells. Therefore, it is a further object of the present invention to disclose the use of these specific types of diterpene for the treatment of AR-associated diseases.